Guideline for the Management of Nephrotic

Syndrome






Scottish Paediatric Renal and Urology Network (SPRUN)



Please note: This guideline is to be assessed using the AGREE
(Appraisal of Guidelines for Research and Evaluation) criteria.




Contents Page
Number(s)
1. Guideline Development
1.1 Guideline Development Group
1.2 Patient population and target audience
1.3 Objectives and clinical questions
1.4 Methodology

2. Definition and diagnosis of idiopathic nephrotic
syndrome

3. Initial assessment and investigation at presentation
4. Initial management
4.1 Drug treatment
4.1.1 Steroids
4.1.2 Antibiotic prophylaxis
4.1.3 Gastroprotection
4.1.4 Albumin infusion
4.2 Dietary and fluid management
4.3 Complications
4.3.1 Hypovolaemia
4.3.2 Hypertension
4.3.3 Infection
4.3.4 Thrombosis
4.4 Monitoring and Observations
4.4.1 Nursing
4.4.2 Laboratory
4.4.3 Response to treatment

5. Indications for referral to Paediatric Nephrology
Service
5.1 Atypical features
5.2 Complications
5.3 Renal biopsy


6. Management of relapsing nephrotic syndrome
6.1 Diagnosis of relapse
6.2 Drug treatment
6.2.1 Steroids
6.2.2 Antibiotic prophylaxis
6.2.3 Gastroprotection
6.3 Dietary and fluid management
6.4 Complications
6.5 Monitoring and Observations
6.5.1 Nursing
6.5.2 Laboratory


7. Frequently relapsing nephrotic syndrome
7.1 Diagnosis of frequent relapse
7.2 Drug treatment
7.2.1 Alternate day steroids
7.2.2 Levamisole


7.2.3 Cyclophosphamide
7.2.4 CNI Ciclosporin (or Tacrolimus)
7.2.5 Mycophenolate Mofetil
7.2.6 Rituximab IV
7.3 Diet and fluids
7.4 Monitoring and Observations

8. Dietary and Nutritional Management
9. Vaccination advice
9.1 Varicella
9.2 Pneumococcal
9.3 Live vaccines
9.4 Seasonal influenza and H1N1

10. Patient and Family Preparation
10.1 Patient and Family Education
10.2 Patient information provision and links

11. Pre-discharge Checklist
11.1 Parent training on urine monitoring
11.2 Pre-discharge education and planning
checklist:

12. Outpatient Management and Follow-up
12.1 Monitoring
12.1.1 Growth
12.1.2 Blood pressure
12.1.3 Steroid side effects
12.1.4 Ophthalmology review
12.1.5 Varicella status
12.1.6 Second line therapy monitoring
12.2 Standards for laboratory and clinical indices
12.2.1 Urine P:CR
12.2.2 Drug level monitoring

13. Future Guideline Development
Appendix 1
Appendix 2
References


1. Guideline Development

1.1 Membership of Guideline Development Group

Consultant Paediatrician
Senior Staff Nurse/Paediatric Nurse Specialist
Renal Nurse Specialist
Consultant Paediatric Nephrologist
Paediatric Renal Pharmacist
Renal Dietician
Consultant Microbiologist
Parent Representative

1.2 Patient population and target audience

This document provides information on the investigation, treatment and
management of nephrotic syndrome in children at initial presentation and in
relapse of the condition. The guideline applies to children throughout Scotland
with typical idiopathic nephrotic syndrome. The guideline may not be relevant to
the management of children with atypical presentations and does not apply to
children with congenital nephrotic syndrome, steroid resistant nephrotic
syndrome and nephrotic syndrome secondary to other systemic disease (e.g.
SLE) or other structural glomerular disease (e.g. Alport Syndrome).

This document is intended for use by all health professionals (for example,
doctors, nurses, dieticians and pharmacists) who look after children with
nephrotic syndrome within Scotland.

1.3 Objectives and clinical questions

Guideline objectives:
1. Describe typical and atypical presenting clinical features of idiopathic
nephrotic syndrome of childhood likely to respond to treatment with
steroids.
2. Provide guidance for the safe and effective clinical management of the
initial presentation of children with typical idiopathic nephrotic syndrome
to a general paediatric department.
3. Provide guidance for the safe and effective clinical management of
subsequent relapses in children with typical idiopathic nephrotic syndrome
to a general paediatric department.
4. Provide guidance on the clinical management of complications of
idiopathic nephrotic syndrome.
5. Provide guidance on the indications for referral for specialist nephrology
advice and review of complications of idiopathic nephrotic syndrome.
6. Provide guidance on the indications for referral for specialist nephrology
advice and review of relapsing idiopathic nephrotic syndrome and its
management.
7. Provide guidance on follow up in the general paediatric clinic setting.

8. Provide adequate information and training for children and their families
on idiopathic nephrotic syndrome, its treatment (medication, dietary),
home monitoring and planned follow up.


Clinical questions answered by the guideline:
1. What is the recommended approach to initial investigation and diagnosis?
2. What are the referral criteria for atypical cases?
3. What is an appropriate initial steroid treatment regimen?
4. What other management strategies are recommended at initial
presentation
5. What are the best-practice treatments of complications of nephrotic
syndrome?
a. Use of albumin infusion
b. Management of hypertension
c. Treatment of infection
d. Venous thrombosis
6. What are the recommended management strategies for relapsing
nephrotic syndrome?
7. What follow-up and monitoring do nephrotic syndrome patients require?

1.4 Methodology

This guideline was based on the RHSC, Glasgow Guidelines on the Management
of Nephrotic Syndrome (2005). Best evidence was used to inform
recommendations including Cochrane Collaboration reviews, literature searches
of PubMed, using the terms paediatric / children, nephrotic syndrome, and
steroid sensitive. Evidence based on double blind randomised control trials
was deemed to be the best level of evidence, and expert opinion where no other
form of evidence was available. Only articles written in English were included.

Recommendations were based on consensus of opinion from the working group.
There were no areas of disagreement.



2. Definition of Nephrotic Syndrome
Nephrotic range proteinuria (uProtein:Creatinine P:CR >200mg/mmol
Creatinine> 1g/m
2
/day;)
Hypoalbuminaemia (<25 g/l)
Generalised oedema

Classification
Idiopathic (primary) nephrotic syndrome
o Minimal change (80-90%)
o Focal segmental glomerulosclerosis (FSGS) (10-20%)

Secondary nephrotic syndrome (HSP, SLE, MPGN)
Congenital nephrotic syndrome

This document relates only to the management of idiopathic nephrotic
syndrome. Children who present with the typical features of nephrotic
syndrome (see below) are generally responsive to steroid treatment and are
likely to show minimal changes on histology, although biopsy is not usually
indicated.
Therefore children with typical features are started on steroids without recourse
to renal biopsy.
Those with atypical features are more likely to be unresponsive to steroid
treatment and a biopsy more likely to show FSGS or other forms of nephrotic
syndrome. Those with atypical features should be discussed with a paediatric
nephrologist as they may merit renal biopsy before receiving steroid treatment.



Nephrotic Syndrome
Typical Features Atypical Features
Age 1-10 years <1yr, >10years
Normotensive Hypertensive
Normal Renal Function Elevated Creatinine
+/- microscopic haematuria ( in xx%) Macroscopic Haematuria
systemic disease symptoms







3. Initial Assessment and Investigation at presentation
Hypovolaemia
The initial examination of children with nephrotic syndrome needs to
include an assessment of their intravascular volume. Whilst these children
may be very oedematous, they may also be intravascularly depleted.
Signs of intravascular depletion are cool peripheries (capillary refill time >
2 secs), a core-peripheral temperature gap of > 2
o
C, and tachycardia.
Hypotension is a late sign of hypovolaemia, but paradoxical hypertension
may be present. A urinary sodium of < 10 mmol/l is a useful investigation
to confirm hypovolaemia.
If clinically shocked give 10ml/kg 4.5% albumin. Children should be
closely monitored during an albumin infusion, and unless needed for
emergency management it should be administered when medical support
readily available.
If there is evidence of hypovolaemia, give 1 g/kg 20% albumin (5ml/kg)
over 4 - 6 hours. Give 2mg/kg of iv frusemide mid-infusion.

Hypertension
Paradoxical: volume resuscitation
Volume overload: diuretic
Ca+ channel blocker
Short acting nifedipine
Long acting amlodipine

Infection
Loss of complement components and immunoglobulins results in an
increased risk of infection. For antibiotic prophylaxis whilst patients have
significant proteinuria.

Renal vein thrombosis
Loss of proteins such as anti-thrombin III contributes to a pro-coagulant
state. This might be exacerbated by hypovolaemia.
Renal Doppler USS and specialist referral if suspicion.


The following investigations should be performed in all children:
Blood: FBC, U+Es; Creatinine; LFTs; ASOT; C3/C4; Varicella titres
Urine: Urine culture and Urinary protein:creatinine ratio (uPCR)
BP
Urinalysis including glucose
A urinary sodium concentration can be helpful in those at risk of
hypovolaemia.
Varicella status should be known in all children commencing steroids.
Hepatitis B status may be appropriate in children at high risk.



4. Initial Management of First Presentation of Typical
Idiopathic Nephrotic Syndrome


4.1 Drug Treatment

4.1.1 Prednisolone
When the diagnosis of nephrotic syndrome has been made, prednisolone
treatment can be started in children with typical features. Children with atypical
features should be discussed with a paediatric nephrologist when renal biopsy
may be considered first (see above/below).

There is increasing evidence that longer initial courses of prednisolone are
associated with a lower incidence of relapse. Further studies are in progress to
identify any increase in side effects with longer initial courses. Also it is not clear
whether increased initial treatment leads to a reduction in the use of second line
treatments for relapsing steroid sensitive nephrotic syndrome. Currently a 12-
week initial course is recommended. The dose of prednisolone is based on
surface area.

60 mg/m
2
/day for 4 weeks (maximum 80 mg)
40 mg/m
2
/on alternate days for 4 weeks (maximum 60mg)
Reduce dose by 5-10mg/m
2
each week for another 4 weeks then stop

Prednisolone can be given as a single dose in the morning with food, or as
divided doses during the day, particularly if the dose is large.
Patients should be issued with a steroid warning card.
Side effects and risks of steroid treatment should be discussed.
Varicella status should be documented clearly in the case notes and on any
electronic patient record.


4.1.2 Antibiotic Prophylaxis Penicillin V
Whilst nephrotic, children are at increased risk of infection, particularly with
encapsulated organisms such as pneumococcus. There is no evidence that
antibiotic prophylaxis is of benefit, and some centres do not use prophylaxis.
Penicillin V can be given while there is proteinuria and discontinued when the
child goes into remission. Grossly oedematous children are at risk of cellulitis
and may benefit from antibiotic prophylaxis.
Pneumococcal vaccination is recommended for children with NS. Consider giving
at the time of diagnosis.

4.1.3 Gastroprotection
Protection against steroid induced gastric irritation should be considered.

Ranitidine 2mg/kg twice daily for the duration of steroid treatment.
Omeprazole - dose

4.1.4 Albumin Infusion
Clinical indications for albumin include
Clinical hypovolaemia (see earlier)
Symptomatic oedema
skin compromise
cellulitis
Primary peritonitis
Respiratory compromise pleural effusions

A low serum albumin alone is not an indication for intravenous albumin.


If there is evidence of hypovolaemia, give 1 g/kg 20% albumin (5ml/kg) over 4 -
6 hours. Give 2mg/kg of iv frusemide mid-infusion and repeat at end unless
good diuretic response in progress.

If clinically shocked give 10ml/kg 4.5% albumin. Children should be closely
monitored during albumin infusions, and where possible they should be
administered during working hours.



4.2 Dietary and Fluid Management
A low salt diet is used to try to prevent further fluid retention and oedema. Fluid
restriction may also be helpful. These restrictions are lifted once the child goes
into remission.
Dietetic advice re calorie control while on steroids.

4.3 Complications
The main complications of nephrotic syndrome are hypovolaemia, infection and
thrombosis.

4.3.1 Hypovolaemia
The initial examination of children with nephrotic syndrome needs to include an
assessment of their intravascular volume. Whilst these children may be very
oedematous, they may also be intravascularly depleted. Signs of intravascular
depletion are cool peripheries (capillary refill time > 2 secs), a core-peripheral
temperature gap of > 2
o
C, and tachycardia. Hypotension is a late sign of
hypovolaemia, but paradoxical hypertension may be present. A urinary sodium
of < 10 mmol/l is a useful investigation to confirm hypovolaemia.
If there is evidence of hypovolaemia, give 1 g/kg 20% albumin (5ml/kg) over 4 -
6 hours. Give 2mg/kg of iv frusemide mid-infusion.



4.3.2 Hypertension
Paradoxical: volume resuscitation
Volume overload: diuretic
Steroid induced
Ca+ channel blocker
Short acting nifedipine
Long acting amlodipine

Hypertension is unusual in the acute setting and if persistent should lead to
reconsideration of other possible underlying glomerulonephritis.


4.3.3 Infection
Loss of complement components and immunoglobulins results in an increased
risk of infection. Consider antibiotic prophylaxis whilst patients have significant
proteinuria.
Cellulitis
History of recent VZ exposure
Primary Varicella Zoster infection
Herpes Zoster infection (Shingles)

4.3.4 Thrombosis
Loss of proteins such as anti-thrombin III contributes to a pro-coagulant state.
This might be exacerbaterd by hypovolaemia. Information here on clinical
features to watch for.


4.4 Monitoring and Observations
Admission and in-patient management is often necessary with the first
presentation. Regular review to monitor for complications and to assess the
onset of remission is needed. Parental teaching and education (see below) can
take place at the same time

4.4.1 Nursing
At admission

During in patient admission

Discharge preparation??

4.4.2 Laboratory
Daily urine P:CR
Renal biochemistry in patients requiring IV albumin and diuretics.
Renal biochemistry if evidence of impaired glomerular function.
Drug level monitoring if aminoglycoside/vancomycin therapy.



4.4.3 Response to treatment
Diuresis and weight reduction
Reduction in Albustix positive level
Reduction in daily urine P:CR

Most children with nephrotic syndrome will respond to steroid treatment within
2-4 weeks. A remission is defined as 3 or more days of trace or negative on
dipstick testing. Treatment is continued for a total of 12weeks as outlined above.
If proteinuria persists beyond the first 4 weeks of steroid treatment, then
children should be referred for renal biopsy.



5. Indications for Referral to Paediatric Nephrology Service

5.1 Atypical Features
Age < 1 yr
Age > 10-12 yrs
Persistent hypertension
Elevated creatinine not associated with pre-renal uraemia
Macroscopic haematuria
Low C3/C4
Systemic disease symptoms and signs

Failure to respond to steroids within 4 weeks

5.2 Complications
Severe pre-renal renal failure
Renal vein thrombosis

5.3 Renal Biopsy

Renal biopsy is considered mandatory in children unresponsive to steroids
following at least 28 days treatment with Prednisolone at a dose of 60
mg/m
2
/day (maximum 80 mg). Histology appearances suggesting other
underlying conditions may alter treatment options.

Those children with atypical features are more likely to be unresponsive to
steroid treatment and a biopsy more likely to show FSGS or other forms of
nephrotic syndrome. Those with atypical features should be discussed with a
paediatric nephrologist as they may merit renal biopsy before receiving steroid
treatment.




6. Management of Relapsing Nephrotic Syndrome
Up to 60 - 70 % of children with nephrotic syndrome may have one or more
relapse.
Typically relapses are triggered by intercurrent illnesses, particularly viral upper
respiratory infections. Families should be aware to be more vigilant at such
times. Low grade proteinuria may occur transiently (up to 2+) and may subside
without steroid as the intercurrent illness settles.

6.1 Diagnosis of Relapse Nephrotic Syndrome
These are diagnosed if there is +++ or ++++ proteinuria for 3 or more days.
Urine should be checked initially twice weekly, then weekly after the first
episode, and the families instructed to get in contact should a relapse of
proteinuria occur, or if there is ++ for more than 1 week.
If there is uncertainty whether there is a full relapse clinical assessment
(weight, BP) for fluid retention, quantitative uPCR and measurement of serum
albumin can be helpful in guiding management: intervention or expectant
observation.
Patients often can be managed as an out patient with regular review while
awaiting remission.

6.2 Drug treatment

6.2.1 Prednisolone
Prednisolone treatment should be restarted once a relapse has been diagnosed.

2mg/kg daily (maximum 80 mg) until the first morning urine is negative or
trace for 3 consecutive days
40 mg/m
2
(maximum 60 mg) on alternate days for 4 weeks then stop or taper
the dose over 4-8 weeks


6.1.2 Antibiotic Prophylaxis Penicillin V
While there is persistent proteinuria (>++) Penicillin V prophylaxis can be given.
Penicillin V can be given while there is proteinuria and discontinued when the
child goes into remission. Grossly oedematous children are at risk of cellulitis
and may benefit from antibiotic prophylaxis.
Pneumococcal vaccination is recommended for children with NS. Check that this
has been administered.

6.2.3 Gastroprotection
Protection against steroid induced gastric irritation should be considered.
Ranitidine 2mg/kg twice daily for the duration of steroid treatment.
Omeprazole - dose

6.3 Dietary and Fluid management
Whilst there is proteinuria (>++) a no added salt diet is advised.
It is also advisable to advise on avoiding an excessively large fluid intake
while awaiting remission. A modest fluid restriction may also be helpful. These
restrictions are lifted once the child goes into remission.
Dietetic advice re calorie control while on steroids.


6.4 Complications
The main complications of nephrotic syndrome are hypovolaemia, infection and
thrombosis. Their management is same as at presentation (see above: section
4.3)


6.5 Monitoring and Observations
Admission is often not necessary with relapse. Early review to monitor for
complications and to assess the onset of remission is needed.

Parental support for first relapses is often welcome and allows teaching to be
reinforced.

6.5.1 Nursing
Role of nurse specialist in local teams?
Monitoring progress
Clinical assessment fluid retention; complications
Weight
BP
Daily EMU stix (uPC:R see below)
Fluid balance advice


6.5.2 Laboratory
Where clinical uncertainty on relapse status:
urine P:CR
Renal biochemistry including serum albumin.



7. Further management of patients with Frequent Relapses



7.1 Diagnosis of frequent relapse
Frequent relapses are defined as:

2 or more relapses within the first 6 months of presentation
4 or more relapses within any 12 month period
This becomes steroid dependency if the relapses while still on steroids or
within 2 weeks of ceasing steroids.

If children have frequent relapses, strategies should be adopted to try to reduce the amount
of steroid required.


7.2 Drug treatment

7.2.1 Low Dose Alternate Day Prednisolone
Low dose alternate day steroid treatment (< 10-15 mg/alt days) may prevent
relapses, and result in less steroid being given overall.
Referral for discussion of second line therapy with a Paediatric Nephrologist is indicated in
children with
Frequent relapses
Steroid dependency
Steroid toxicity




7.2.2 Levamisole
Levamisole may be beneficial for children who have occasional relapses. It is less
useful for children who are steroid dependent. The dose is 2.5 mg/kg/ on alt
days . Wean steroid regiment when treatment established for at least 4 weeks.
If successful it can be continued of periods up to 3 years.
Reversible idiosyncratic neutropenia is a rare but recognised side-effect. Also
rash (erythema multiforme like) and GI intolerance may rarely limit use. A FBC
should be checked monthly for the first 3 months.
This drug is not licensed in the UK, and has to be imported.

7.2.3 Cyclophosphamide
For children with frequent relapses or those who are steroid dependent consider
a course of Cyclophosphamide 3 mg/kg/day for 8 weeks or equivalent. It is best
to avoid cutting the tablets. FBC should be monitored for the first few weeks of
treatment.

7.2.4 Calcineurin Inhibitors Ciclosporin (or Tacrolimus)
Ciclosporin at a dose of 2.5 mg/kg bid usually for 1 year may be useful as a
steroid sparing agent. Levels should be checked after 1-2 weeks; aim for a 12
hour trough of 70 120 nmol/l. For children under 5 yrs of age, three times
daily dosing may be necessary. Monitor BP and renal function.



7.2.5 Mycophenylate Mofetil (MMF)
There is some experience of using MMF in children with difficult to treat NS. It
may be useful for those children showing signs of cyclosporin toxicity. Doses of
600mg /m
2
/bid have been used. FBC should be monitored for leucopenia. The
use of MMF is associated with gastro-intestinal intolerance, mainly diarrhoea.
This is an unlicensed indication for MMF.

7.2.6 Rituximab
New experimental therapy.

8. Dietary and nutritional management



9. Vaccination Advice
Pneumococcal
Confirm status
Recommended for all unvaccinated children with NS.
If not administered
Administer with first admission OR
Refer to GP to have Prevenar/Pneumovax.


Varicella status non-immune
Consider giving varicella vaccine between relapses in children
with frequent relapses who are varicella seronegative. Aim to
administer vaccine when prednisolone dose is low.
ZIG (passive immunity) for exposure prophylaxis as per DH
guidelinesImmunisation against Infectious Disease - DH
Green Book
Active disease admission for IV aciclovir then p.o.
valaciclovir when no new crops of vesicles.
Active immunisation when off immunosuppression
Varicella status should be repeated 6 monthly in those who
are non-immune.

Annual seasonal flu vaccination recommended
Inform GP

H1N1 vaccination as recommended by Chief Medical Officer for high risk
groups
Inform GP



10. Patient and Family Preparation

10.1 Patient and Family Education

10.2 Patient and Family Information Provision and Links



11. Pre-discharge checklist


12. Out-patient management and follow-up


12.1 Clinical monitoring
For children on long-term steroids monitor for side effects:
1) Monitor BP at each clinic visit and chart against casual BP centile chart.
2) Monitor growth (including bone age and pubertal stage where appropriate)
3) Monitor weight dietetic review where appropriate
4) Glycosuria / HbA1c
5) Bone mineral density / calcium supplements
6) Ophthmology review

7) Varicella status should be repeated 6 monthly in those who are non-immune.

8) Patients on second line therapy require monitoring as specified for
treatment regimen above (section 7).

12.2 Standards for laboratory monitoring



13. Future guideline development

Future review of this guideline is due every 2 years (insert date) or at an earlier
date to incorporate clinically significant changes in practice. This guideline will
be audited prior to its review to assess the impact of implementation of the
guideline, and to determine changes required to improve patient outcomes.

Audit of the guideline may cover:


Appendix 1

Appendix 2 etc.

Reference list